Abstract Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of California, San Diego and Laureate Institute for Brain Research is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (5/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1086 9-10 year olds enriched for high- risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD- USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the ?gateway interactions? between use of different substances. This hub?s Research Project focuses on mechanisms of substance use disorder, special populations with high use prevalence, and the use of drugs other than marijuana. (1) We will determine whether individual differences in neural processing of antireward (i.e., negative reinforcement mechanisms) in amygdala, insula, and anterior cingulate are associated with increased negative emotionality and pain, predict initiation of use and problem use, and are in turn further dysregulated by substance use. (2) We will determine whether protective environment factors and ethnic identification in minority youth are linked to healthier antireward processing and better substance use outcomes. (3) We will determine whether antireward neural processing predicts increased use of illicit drugs other than MJ including misuse of prescription drugs, if such use predicts subsequent exaggerated antireward processing, and if gateway interactions exist between substances. Finally, we will use machine learning approaches to develop a youth-specific risk calculator that will enable us to identify individually- based modifiable risk factors, providing brain-based targets of future novel prevention and intervention approaches.